What is the best treatment for breakthrough hypertension resistant to other measures?

Best Treatment for Breakthrough Hypertension Resistant to Other Measures

For breakthrough hypertension resistant to other measures, the addition of low-dose spironolactone to existing treatment is the most effective approach when first-line therapies have failed. 1

Definition and Confirmation of Resistant Hypertension

Resistant hypertension is defined as:

• Blood pressure that remains above target (>130/80 mmHg) despite concurrent use of at least three antihypertensive agents 1
• These three medications should include a long-acting calcium channel blocker (CCB), a blocker of the renin-angiotensin system (ACE inhibitor or ARB), and a diuretic at maximal or maximally tolerated doses 1, 2

Before proceeding with additional treatments, it's crucial to:

• Confirm true treatment resistance by performing 24-hour ambulatory BP monitoring to exclude white-coat effect 1
• Assess medication adherence (a major cause of apparent resistance) 1
• Evaluate for secondary causes of hypertension 1

Treatment Algorithm for Resistant Hypertension

Step 1: Optimize Current Regimen and Lifestyle Modifications

• Ensure sodium restriction (<2400 mg/day) 1
• Maximize lifestyle interventions (weight loss, exercise, dietary modifications) 1
• Ensure appropriate diuretic type for kidney function 1

Step 2: Optimize Diuretic Therapy

• Substitute an optimally dosed thiazide-like diuretic (chlorthalidone or indapamide) for the prior diuretic 1

Step 3: Add Mineralocorticoid Receptor Antagonist

• Add low-dose spironolactone to existing treatment 1
• This is the most effective fourth-line agent based on current evidence 2

Step 4: Alternative Options if Spironolactone is Not Tolerated

• Use eplerenone instead of spironolactone 1
• Add further diuretic therapy (amiloride, higher dose thiazide/thiazide-like diuretic, or loop diuretic) 1
• Add beta-blocker (e.g., bisoprolol) if not already indicated 1
• Consider alpha-blocker (e.g., doxazosin) 1

Step 5: Additional Options for Persistent Resistance

• Add centrally acting BP-lowering medication 1
• Consider hydralazine (starting at 25 mg three times daily) 1
• For severe cases, minoxidil may be substituted for hydralazine 1

Step 6: Device-Based Therapies

• For patients with uncontrolled BP despite a three BP-lowering drug combination, catheter-based renal denervation may be considered 1, 3
• This should only be performed at medium-to-high volume centers after shared risk-benefit discussion and multidisciplinary assessment 1, 3

Special Considerations for Acute Hypertensive Episodes

For severe hypertension requiring immediate intervention:

• IV labetalol, oral methyldopa, or nifedipine are recommended first-line agents 1
• IV hydralazine is a second-line option 1
• In acute intracerebral hemorrhage with SBP ≥220 mmHg, careful acute BP lowering with IV therapy to <180 mmHg should be considered 1

Population-Specific Considerations

Ethnic Differences

• In Black patients, initial antihypertensive treatment should include a diuretic or a CCB, either alone or with a RAS blocker 1
• For Black patients from Sub-Saharan Africa, combination therapy including a CCB with either a thiazide diuretic or a RAS blocker should be considered 1

Comorbidities

• Heart Failure: Treatment should include ACE inhibitor/ARB, beta-blocker, diuretic, and/or mineralocorticoid receptor antagonist 1
• Chronic Kidney Disease: Target SBP 120-129 mmHg if eGFR >30 mL/min/1.73m² 1
• Stroke/TIA: Target SBP 120-130 mmHg 1

Common Pitfalls and Caveats

• Pseudo-resistance is common and must be excluded before diagnosing true resistant hypertension 1
• Poor medication adherence accounts for approximately 50% of apparent treatment resistance 1
• High sodium intake significantly contributes to treatment resistance 1
• Medications like NSAIDs, certain antidepressants, and stimulants can interfere with BP control 1
• Monitoring for electrolyte abnormalities is essential when using mineralocorticoid receptor antagonists 1

Emerging Therapies

Recent research has identified promising new drug classes for resistant hypertension:

• Non-steroidal mineralocorticoid receptor antagonists (finerenone, esaxerenone, ocedurenone) 4, 2
• Selective aldosterone synthase inhibitors (baxdrostat) 2
• Dual endothelin receptor antagonists (aprocitentan) 4, 2

These newer agents may provide additional options for patients with true resistant hypertension who have not responded to conventional therapies 4, 2.